Age-related macular degeneration (AMD) causes progressive impairment of central vision and is the leading cause of irreversible vision loss in older Americans (Swaroop A et al., 2007, Hum Mol Genet 16 Spec 2:R174-82). Some subjects with dry AMD will have the disease progress into neovascular or exudative AMD, which usually results in blindness. The neovascular or exudative form of AMD is also referred to as wet AMD. Other patients with dry AMD may progress to central geographic atrophy of the retina. Wet AMD and central geographic atrophy are both classified as “advanced AMD”.
Although the etiology of AMD remains largely unknown, implicated risk factors include: age, ethnicity, smoking, hypertension, obesity and diet (Ambati J et al., 2003, Surv Ophthalmol 48(3):257-93). Familial aggregation (Klayer C C et al., 1998, Arch Ophthalmol 116(5):653-8), twin studies (Hammond C J et al., 2002, Ophthalmology 109(4):730-6), and segregation analysis (Heiba I M et al., 1994, 11(1):51-67) suggest that there is also a significant genetic contribution to the disease. The candidate gene approach and genome-wide association studies have consistently implicated the complement factor H (CFH), third component of complement (C3) and second component of complement/factor B (C2/BF) genes, all members of the complement-mediated inflammatory cascade, as well as Age-Related Maculopathy Susceptibility 2 (ARMS2), a gene likely involved in mitochondria-associated pathways.
Much progress has been made in identifying and characterizing the genetic basis of AMD. In a remarkable example of the convergence of methods for disease gene discovery, multiple independent research efforts identified the Y402H variant in the complement factor H (CFH [(MIM 134370]) gene on chromosome 1q32 as the first major AMD susceptibility allele (Haines J L et al., 2005, Science 308(5720):419-21; Hageman G S et al., 2005, Proc Natl Acad Sci USA 102(20):7227-32; Klein R J et al., 2005, Science 308(5720):385-9; Edwards A O et al., 2005, Science 308(5720):421-4; Zareparsi S et al., 2005, Am J Hum Genet 77(1):149-53; Jakobsdottir J et al., 2005, Am J Hum Genet 77(3):389-407). While one of the studies was able to pinpoint CFH on the basis of a whole-genome association study (Klein R J et al., supra), most studies focused on the 1q32 region because it had consistently been implicated by several whole-genome linkage scans. More recently, disease associated haplotypes within the CFH gene have also been shown to be associated with AMD (Li M et al., 2006, Nat Genet 38(9):1049-54). A second genomic region with similarly consistent linkage evidence is chromosome 10q26, which was identified as the single most promising region by a recent meta-analysis of published linkage screens (Fisher S A et al., 2005, Hum Mol Genet 14(15):2257-64).
The Age-Related Eye Disease Study (AREDS), sponsored and conducted by the National Eye Institute in the United States, provided descriptive data on the clinical course of AMD and attempted to identify factors that influence the development of early disease and progression and evaluated the potential efficacy of high-dose vitamins and minerals to arrest or retard disease progression. AREDS was a long-term multicenter, prospective study of 4757 persons age 55 to 80 years that assessed the clinical course, prognosis, and risk factors of AMD.
The study was designed to document the clinical course of AMD and determine progression risk determinants through the collection of data on possible risk factors, Changes in visual acuity, photographically documenting changes in the macula and self-reported visual function were recorded at regular intervals. A grading system was developed for each of the lesions of AMD. The major AMD outcomes in this study were the development of neovascular disease or the development of geographic atrophy that involves the center of the macula. Eyes developing either of these conditions were considered to have progressed to advanced AMD. Early lesions of AMD, particularly drusen (size, type, and extent) and RPE abnormalities (detachment, atrophy, and pigment disturbances) were graded individually for each study eye.
At the time of the AREDS study design there was evidence for the beneficial effect of elemental zinc for AMD. The study was designed to determine if zinc, alone or in combination with a vitamin/antioxidant formulation could slow the progression of AMD. Formulations that included zinc included copper to prevent zinc-induced copper-deficiency anemia. Study participants at risk of vision loss with early AMD received combinations of the zinc formulation and the vitamin/antioxidant formulation. Participants without drusen or RPE changes were never assigned to the zinc formulation. Remaining participants (3640) were enrolled in a 2×2 factorial design of antioxidants and zinc.
The results of the AREDS Study were reported in 2001 (see AREDS report no. 8, Arch Ophthalmol 119:1417-36, 2001, which is incorporated herein in its entirety). The average follow-up of the 3640 enrolled study participants, aged 55-80 years, was 6.3 years, with 2.4% lost to follow-up. Compared with placebo, treatment with antioxidants plus zinc demonstrated a statistically significant odds reduction for the development of advanced AMD (odds ratio [OR], 0.72; 99% confidence interval [CI], 0.52-0.98). The ORs for zinc alone and antioxidants alone are 0.75 (99% CI, 0.55-1.03) and 0.80 (99% CI, 0.59-1.09), respectively. Participants with extensive small drusen, nonextensive intermediate size drusen, or pigment abnormalities had only a 1.3% 5-year probability of progression to advanced AMD. Odds reduction estimates increased when these 1063 participants were excluded (antioxidants plus zinc: OR, 0.66; 99% CI, 0.47-0.91; zinc: OR, 0.71; 99% CI, 0.52-0.99; antioxidants: OR, 0.76; 99% CI, 0.55-1.05). Both zinc and antioxidants plus zinc significantly reduced the odds of developing advanced AMD in this higher-risk group. The only statistically significant reduction in rates of at least moderate visual acuity loss occurred in persons assigned to receive antioxidants plus zinc (OR, 0.73; 99% CI, 0.54-0.99). No statistically significant serious adverse effect was associated with any of the formulations.
As a result of the findings of AREDS study, subjects or patients that present with the symptoms of dry AMD are routinely prescribed zinc and antioxidant containing vitamins to slow or prevent the onset of wet AMD. The genetic profile of the subject has not been a consideration when prescribing such course of treatment.